Based on our understanding of envelope-based mechanisms of humoral evasion, we are working to design envelope-based immunogens with these mechanisms disabled. Such modified immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised protein scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through structural searches of the entire Protein Data Bank (PDB). Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves resurfacing, where the surface of a molecule, not involved in eliciting a desired response, is altered between prime and boost phases of immunization. We have also begun to couple epitope mimics to highly immunogenic carrier proteins or to display epitope mimics in the context of self-assembling nanoparticles, which have substantially higher immunogenicity than monovalent or even trivalent immunogens. In addition to such designer immunogens, we have also been investigating how insights from B cell ontogeny of broadly neutralizing antibodies can identify difficult steps in the elicitation process, which might be influenced by immunization; such antibody-lineage based design seeks to exploit our understanding of the specific developmental processes that a target lineage requires to achieve neutralization - and to re-elicit similar antibodies in the general population through antibody-lineage based design.